This invention is in the area of organic compounds with antiviral activity, and in particular provides a process for the preparation of enantiomerically pure .beta.-D-dioxolane nucleosides, and methods for the treatment of viral diseases that includes administering an effective amount of one or more of the described compounds.
A number of 2',3'-dideoxynucleosides have been found to be potent antiviral agents against human immunodeficiency virus (HIV), the causative agent of acquired immunodeficiency syndrome (AIDS). AZT (3'-azido-2'-deoxythymidine, Mitsuya, H.; Broder, S. Proc. Natl. Acad. Sci. U.S.A., 1986 83, 1911) was the first compound approved by the U.S. Food and Drug Administration for the treatment of patients with AIDS or AIDS-related complex. Other synthetic nucleosides have now either been approved or are undergoing various stages of clinical trials, including 2',3'-dideoxyinosine (DDI), 2',3'-dideoxycytidine (DDC) (see Yarchoan, R. et. al., Science, 1989, 245, 412), and 2'-fluoro-arabinofuranosyl-2'-3'-dideoxycytidine (Martin, T. A., et al., J. Med. Chem., 1990, 33, 2137; Watanabe, K. A., et al., J. Med. Chem., 1990, 33, 2145; Sterzycki, R. Z., et al., J. Med. Chem., 1990 33, 2150).
After cellular phosphorylation to the 5'-triphosphate by cellular kinases, these synthetic nucleosides may be incorporated into a growing strand of viral DNA, causing chain termination due to the absence of the 3'-hydroxyl group.
The stereochemistry of nucleoside derivatives play an important role in their biological activity. The C1' position of the ribose in the nucleoside (the carbon bound to the nitrogen of the heterocyclic base) is a chiral center because the carbon is attached to four different moieties. Likewise, there is an optically active center at C4' of the nucleoside (the ring carbon bound to the hydroxymethyl group that is phosphorylated in nucleotides). In the naturally occurring nucleosides, both the base attached to the C1' and the hydroxymethyl group attached to the C4' atom are in the .beta.-configuration (above the plane of the sugar). The corresponding non-naturally occurring a-isomers (in which the moieties are below the plane of the sugar) are rarely biologically active, and are typically toxic.
An analysis of the solid-state conformations of six active and two inactive anti-HIV nucleoside agents was recently performed to attempt to correlate the presence or absence of certain stereochemical features with high HIV activity. Van Roey, P., et al., J. Am. Chem. Soc., 1988, 110, 2277; and Van Roey, P., et al., Proc. Natl. Acad. Sci. U.S.A., 1989, 86, 3929.
There has been recent interest in the synthesis of nucleoside derivatives in which the 3'-carbon of the nucleoside has been replaced with a heteroatom. Norbeck, D. W., et al., in Tet. Lett., 1989, 30, 6263, reported the synthesis of (.+-.)-1-(2.beta.,4.beta.)-2-(hydroxymethyl)-4-dioxolanyl!thymine (referred to below as (.+-.)-dioxolane-T, see FIG. 1), that results in a racemic mixture of diastereomers about the C4' atom. The product is a derivative of 3'-deoxythymidine in which the C3' atom has been replaced with an O3' atom. The product was synthesized in five steps from benzyloxyaldehyde dimethylacetal and (.+-.)-methyl glycerate to produce a 79% yield of the 1:1 diastereomeric mixture. The X-ray crystallographic analysis of the product revealed that the dioxolane ring adopts the .sup.3 T.sub.4 conformation commonly observed in ribonucleosides, with the O3' atom in the endo position. Norbeck reported that the racemic mixture of dioxolane-T exhibits an anti-HIV activity of 20 .mu.M in ATH8 cells, and attributed the low efficacy against the virus to an effect of the endo conformation of the O3' atom. Tetrahedron Letters 30 (46), 6246, (1989).
European Patent Application Publication No. 0 337 713 and U.S. Pat. No. 5,041,449, assigned to IAF BioChem International, Inc., disclose that a generic formula of 2-substituted-4-substituted-1,3-dioxolanes exhibit antiviral activity.
Belleau, et al., in the Fifth International Conf. on AIDS, Montreal, Canada Jun. 4-9, 1990, paper No. T.C.O.1., reported a method of synthesis of cytidine nucleosides that contain oxygen or sulfur in the 3'-position. The dioxolane ring was prepared by the condensation of RCO.sub.2 CH.sub.2 CHO with glycerin. As with the Norbeck synthesis, the Belleau synthesis results in a racemic mixture of diastereoisomers about the C4' carbon of the nucleoside. Belleau reported that the sulfur analog, referred to as NGBP-21 or (.+-.) BCH-189 (see FIG. 1), has anti-HIV activity.
European Patent Application No. 92300056.6 to Belleau discloses the use of BCH-189 for the treatment of hepatitis B virus (HBV). BCH-189 is now in clinical trials under the supervision of the U.S. Food and Drug Administration.
U.S. Pat. No. 5,047,407 and European Patent Application Publication No. 0 382 526, also assigned to IAF Biochem International, Inc. disclose that a generic formula of 2-substituted-5substituted-1,3-oxathiolane nucleosides have antiviral activity.
As of the priority date of this application, a method of synthesis of a nucleoside analog with an oxygen in the 3'-position that results in an enantiomerically pure dioxolane nucleoside that has the same stereochemistry as the nucleosides found in nature (the .beta. stereoisomer) has not been reported. There is a need for such a synthesis as a research tool to provide more information on the effect of stereochemistry on the anti-viral activity of nucleoside derivatives, and to provide new anti-HIV agents.
It is therefore an object of the present invention to provide a method of synthesis of enantiomerically pure dioxolane nucleosides.
It is another object of the present invention to provide enantiomerically pure dioxolane nucleosides with significant anti-HIV activity.